Oncotarget

Research Papers:

KPNB1-mediated nuclear import is required for motility and inflammatory transcription factor activity in cervical cancer cells

Tamara Stelma and Virna D. Leaner _

PDF  |  HTML  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:32833-32847. https://doi.org/10.18632/oncotarget.15834

Metrics: PDF 1679 views  |   HTML 2526 views  |   ?  


Abstract

Tamara Stelma1 and Virna D. Leaner1

1Division of Medical Biochemistry and Structural Biology, SAMRC Gynaecology Cancer Research Centre, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa

Correspondence to:

Virna D. Leaner, email: Virna.Leaner@uct.ac.za

Keywords: karyopherin/importin, cervical cancer, chemotherapeutic, nuclear import, inflammation

Received: November 18, 2016    Accepted: February 07, 2017    Published: March 02, 2017

ABSTRACT

Karyopherin β1 is a nuclear import protein involved in the transport of proteins containing a nuclear localisation sequence. Elevated Karyopherin β1 expression has been reported in cancer and transformed cells and is essential for cancer cell proliferation and survival. Transcription factors such as NFĸB and AP-1 contain a nuclear localisation sequence and initiate the expression of multiple factors associated with inflammation and cancer cell biology. Our study investigated the effect of inhibiting nuclear import via Karyopherin β1 on cancer cell motility and inflammatory signaling using siRNA and the novel small molecule, Inhibitor of Nuclear Import-43, INI-43. Inhibition of Karyopherin β1 led to reduced migration and invasion of cervical cancer cells. Karyopherin β1 is essential for the translocation of NFĸB into the nucleus as nuclear import inhibition caused its cytoplasmic retention and decreased transcriptional activity. A similar decrease was seen in AP-1 transcriptional activity upon Karyopherin β1 inhibition. Consequently reduced interleukin-6, interleukin-1 beta, tumour necrosis factor alpha and granulocyte macrophage colony stimulating factor expression, target genes of NFkB and AP-1, was observed. Migration studies inhibiting individual transcription factors suggested that INI-43 may affect a combination of signaling events. Our study provides further evidence that inhibiting KPNB1 has anti-cancer effects and shows promise as a chemotherapeutic target.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 15834